Arthrogryposis, Distal, Type 2a

A number sign (#) is used with this entry because of evidence that distal arthrogryposis type 2A (DA2A) is caused by heterozygous mutation in the MYH3 gene (160720) on chromosome 17p13.

Mutations in this gene can also cause distal arthrogryposis type 2B (DA2B; 601680), also known as Sheldon-Hall syndrome.

Description

Freeman-Sheldon syndrome (FSS), or DA2A, is phenotypically similar to DA1. In addition to contractures of the hands and feet, FSS is characterized by oropharyngeal abnormalities, scoliosis, and a distinctive face that includes a very small oral orifice (often only a few millimeters in diameter at birth), puckered lips, and an H-shaped dimple of the chin; hence, FSS has been called 'whistling face syndrome.' The limb phenotypes of DA1 and FSS may be so similar that they can only be distinguished by the differences in facial morphology (summary by Bamshad et al., 2009).

For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).

Clinical Features

In craniocarpotarsal dystrophy, a syndrome first described by Freeman and Sheldon (1938), certain skeletal malformations are associated with facial characteristics. The main skeletal malformations include camptodactyly with ulnar deviation, talipes equinovarus, and an abnormal x-ray appearance of the floor of the anterior cranial fossa of the skull. Facial characteristics include deep-sunken eyes with hypertelorism, increased philtrum length, small nose and nostrils, and a small mouth. Rintala (1968) described a case. He accepted only the cases of Freeman and Sheldon (1938) and Otto (1953) as 'genuine.' Steep anterior cerebral fossa was striking in his patient. He also pointed out in his and the other patients vertical 'folds of skin in the jaw.' In a study of genetic factors in hand malformations, Temtamy and McKusick (1978) noted the occurrence of this syndrome in 2 generations of 3 different families.

Jacquemain (1966) described congenital windmill vane position of the hand: bilateral ulnar deviation and contracture of fingers 2-5 at the metacarpophalangeal joints with adduction of thumbs. The deformity resembled that of rheumatoid arthritis. Clubfoot was also present. Seven patients were affected in 4 generations. Fourteen of 23 cases in the literature were familial and cases occurred in successive generations with father-to-son transmission. The defect was thought to concern the palmar fascia.

Vanek et al. (1986) presented evidence that FSS should be considered a form of myopathic arthrogryposis. Weinstein and Gorlin (1969) gave a full clinical description and referred to observation of affected father and daughter by Fraser (personal communication). They also suggested 'dysplasia' as more appropriate than 'dystrophy.' Cervenka et al. (1969) provided normal standards for the measurement of oral intercommissural distance in children. Fraser et al. (1970) reported the syndrome in father and son; dramatic pictures of their cases have been published (Gellis et al., 1970).

Autosomal dominant inheritance was well documented by Aalam and Kuhhirt (1972). Jorgenson (1974) reported 2 kindreds consistent with autosomal dominant inheritance and reduced penetrance. Severe scoliosis was present in some affected members of the family reported by Wettstein et al. (1980). Hall et al. (1982) reviewed published cases. Marasovich et al. (1989) described affected mother and daughter, who were observed over periods of 30 and 17 years, respectively.

Zampino et al. (1996) described a sporadic case of the whistling face syndrome in a boy who also had severe hypertonicity, swallowing problems, and cerebellar and brainstem atrophy. The authors suggested that primary brain anomalies may explain many manifestations of the syndrome. They noted that it might be more appropriate to speak about the Freeman-Sheldon spectrum rather than syndrome because of the wide range of clinical manifestations.

Ohyama et al. (1997) described the care of a patient with Freeman-Sheldon syndrome over a period of 10 years. Microstomia was treated with a mouth expander for 2 to 3 hours per day before active orthodontic treatment. Separate impressions were necessary in each quadrant of both upper and lower jaws because of limited opening of the mouth. Orthodontic treatment improved the patient's class II malocclusion, which was accompanied by crowding and a deep bite. The palate was highly arched, the tongue was small, there was congenital absence of the right upper second premolar and 2 lower incisors, and the lower arch was crowded.

Toydemir et al. (1999) described a child with a whistling face phenotype but without limb anomalies. The patient was born to normal, nonconsanguineous parents. Seemingly, whistling face syndrome without limb abnormalities had not previously been reported. However, Gorlin (2000) noted that this situation had been reported by Walbaum et al. (1973) and by Patel and Mahmud (1983).

Lev et al. (2000) described a child born to nonconsanguineous Moroccan Jewish parents who had a whistling face, micrognathia, blepharophimosis, failure to thrive, distal arthrogryposis, hypotonia, and profound mental retardation. MRI scan showed generalized cerebral, cerebellar, and brainstem atrophy at the age of 3 years that had not been present at 6 months. Lev et al. (2000) proposed that there are several distinct syndromes with whistling face and joint contractures: one autosomal dominant with no neurologic involvement, and others recessive with varying degrees of central nervous system involvement.

Mueller and Meyer (2005) reported a 5-year-old Turkish boy who, in addition to the classic features of Freeman-Sheldon syndrome, had bilateral juvenile glaucoma.

Stevenson et al. (2006) analyzed a series of 73 individuals referred with a tentative diagnosis of FSS; only 32 cases (approximately 40%) met the diagnostic criteria for classic FSS. In addition to contractures, common features in these 32 cases included severe scoliosis (85%), strabismus (42%), and hearing loss (30%). Most infants required supplementary feedings via a nasogastric (45%) or gastrostomy tube (17%). Children walked by an average age of 19 months, but approximately 80% required ambulation-assist devices. Each child had an average of approximately 10 surgeries, and anesthetic and/or surgical complications were reported in 50% of individuals, including malignant hyperthermia and hyperpyrexia. All were cognitively normal. Classic FSS was present in the mother in 3 cases and in the father in a fourth case. In the 41 non-FSS cases, the diagnoses included DA2B, or Freeman-Sheldon syndrome variant (601680) in 38, multiple pterygium syndrome (265000) in 1, and unknown in 2. In contrast to individuals with classic FSS, patients with DA2B had a larger oral opening and lacked an H-shaped dimpling of the chin.

Tajsharghi et al. (2008) reported a 4-year-old boy with sporadic DA2A confirmed by genetic analysis (160720.0003). The patient had ptosis, very short stature, small contracted mouth, and proximal and distal joint contractures. Muscle biopsies showed no MYH3 expression, consistent with normal developmental downregulation. Tajsharghi et al. (2008) concluded that distal arthrogryposis associated with MYH3 mutations may cause a severe myopathy during fetal development, resulting in congenital joint contractures, and residual muscle defects manifest as a myopathy after embryonic myosin is downregulated postnatally.

Molecular Genetics

Toydemir et al. (2006) screened 28 FSS probands (7 familial and 21 sporadic) for mutations in genes that encode myosin heavy chains. They found a mutation in the MYH3 gene in 26 of 28 FSS cases, including 12 with an R672H (160720.0001) mutation, 8 with an R672C (160720.0002) mutation, 3 with a de novo missense mutation not involving arg672, and 3 with a T178I (160720.0003) mutation that was also found in 2 patients with DA2B.

Using Freeman-Sheldon syndrome as a proof of concept, Ng et al. (2009) showed that candidate genes for mendelian disorders can be identified by exome sequencing of a small number of unrelated, affected individuals. Based on the 4 patients, they were able to identify the MYH3 gene as the only candidate gene. With 3 affected individuals, they narrowed the candidates to 2 possible genes. The results of Ng et al. (2009) suggested that targeted capture and massively parallel sequencing of exomes will be a powerful tool to identify the genetic cause of rare mendelian disorders.

Genotype/Phenotype Correlations

Beck et al. (2014) analyzed genotype/phenotype correlations in 46 probands with DA2A, including 30 families previously reported by Toydemir et al. (2006). MYH3 mutations were found in 43 families, 39 of which (91%) had 1 of 3 recurrent mutations: T178I (160720.0003), R672C (160720.0002), and R672H (160720.0001). Based on the authors' scoring system of phenotypic features, overall severity varied significantly by genotype (p = 0.0055), with T178I being the most severe and R672C the least. Individuals with T178I were noted to have more severe contractures of the feet and face as well as scoliosis that was often congenital. The T178I mutation was found only in simplex cases, and the R672C mutation was found predominantly in familial cases.

Nomenclature

Bamshad et al. (1996) suggested that FSS should be considered a form of distal arthrogryposis and noted that it is most closely related to distal arthrogryposis type 1. Individuals with DA1 and FSS may have such similar limb phenotypes that they can be distinguished only by differences in facial morphology. Families in which different individuals were diagnosed with DA1 or FSS have been reported (Klemp and Hall, 1995). Bamshad et al. (1996) presented a revised and extended classification of the distal arthrogryposes, and referred to Freeman-Sheldon syndrome as DA2 (later DA2A).

DA2A is distinct from DAIIA (114300), which is also known as Gordon syndrome.